Summary: Integrin beta tail domain
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Integrin Edit Wikipedia article
|Integrin alphavbeta3 extracellular domains|
Structure of the extracellular segment of integrin alpha Vbeta3.
|Integrin alpha cytoplasmic region|
Structure of chaperone protein PAPD.
|Integrin, beta chain|
|Integrin beta 7 cytoplasmic domain: complex with filamin|
crystal structure of the filamin a repeat 21 complexed with the integrin beta7 cytoplasmic tail peptide
Integrins are transmembrane receptors that mediate the attachment between a cell and its surroundings, such as other cells or the extracellular matrix (ECM). In signal transduction, integrins pass information about the chemical composition and mechanical status of the ECM into the cell. Therefore, in addition to transmitting mechanical forces across otherwise vulnerable membranes, they are involved in cell signaling and the regulation of cell cycle, shape, and motility.
Typically, receptors inform a cell of the molecules in its environment and the cell responds. Not only do integrins perform this outside-in signaling, but they also operate an inside-out mode. Thus, they transduce information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment, for example to allow blood coagulation by platelets.
There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all animals and have been found in all animals investigated, from sponges to mammals. Integrins have been extensively studied in humans.
Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cellâcell and cellâmatrix interaction and communication. Integrins bind cell surface and ECM components such as fibronectin, vitronectin, collagen, and laminin.
Integrins are obligate heterodimers containing two distinct chains, called the Î± (alpha) and Î² (beta) subunits. In mammals, eighteen Î± and eight Î² subunits have been characterized, whereas the Drosophila genome encodes only five Î± and two Î² subunits, and Caenorhabditis nematodes possess genes for two Î± subunits and one Î². The Î± and Î² subunits each penetrate the plasma membrane and possess small cytoplasmic domains.
In addition, variants of some of the subunits are formed by differential splicing; for example four variants of the beta-1 subunit exist. Through different combinations of the Î± and Î² subunits, some 24 unique integrins are generated, although the number varies according to different studies.
Integrin subunits span the plasma membrane and in general have short cytoplasmic domains of about 40â70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell plasma membrane, the Î± and Î² chains lie close together along a length of about 23 nm; the final 5 nm N-termini of each chain forms a ligand-binding region for the extracellular matrix (ECM).
The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences. Both Î± and Î² subunits bind several divalent cations. The role of divalent cations in the Î± subunit is unknown, but may stabilize the folds of the protein. The cations in the Î² subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
There are various ways of categorizing the integrins. For example, a subset of the Î± chains has an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor; it is also termed the Î±-I domain). Integrins carrying this domain either bind to collagens (e.g. integrins Î±1 Î²1, and Î±2 Î²1), or act as cell-cell adhesion molecules (integrins of the Î²2 family). This Î±-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the Î² subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bindâat least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter amino acid code).
High resolution structure
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging: membrane proteins are classically difficult to purify, and integrins are also large, complex and linked to many sugar trees ("highly glycosylated"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.
Despite these wide-ranging efforts, the X-ray crystal structure obtained for the complete extracellular region of one integrin, Î±vÎ²3, was a surprise. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below) which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look on the structure is still unknown.
When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the same "bent" conformation revealed by the structural studies described above. One school of thought claims that this bent form prevents them from interacting with their ligands, although bent forms can predominate in high-resolution EM structures of integrin bound to an ECM ligands. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the ECM. In cells, the priming is accomplished by a protein talin, which binds to the Î² tail of the integrin dimer and changes its conformation. The Î± and Î² integrin chains are both class-I transmembrane proteins: they pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the plane of the membrane. Talin binding alters the angle of tilt of the Î²3 chain transmembrane helix in model systems and this may reflect a stage in the process of inside-out signalling which primes integrins. Moreover, talin proteins are able to dimerize and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a focal adhesion. Recently, the Kindlin-1 and Kindlin-2 proteins have also been found to interact with integrin and activate it.
Integrins have two main functions:
- Attachment of the cell to the ECM
- Signal transduction from the ECM to the cell
However, they are also involved in a wide range of other biological activities, including immune patrolling, cell migration, and binding to cells by certain viruses, such as adenovirus, echovirus, hantavirus, and foot and mouth disease viruses.
A prominent function of the integrins is seen in the molecule GPIIbIIIa, an integrin on the surface of blood platelets (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIbIIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
Attachment of cell to the ECM
Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which Î± and Î² subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF, and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins such as talin, vinculin, paxillin, and alpha-actinin. These act by regulating kinases such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin alpha6beta4 is an exception: it links to the keratin intermediate filament system in epithelial cells.
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632 reduces the size of the particle, and it is extremely mechanosensitive.
One important function of integrins on cells in tissue culture is their role in cell migration. Cells adhere to a substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. It is not yet clear whether cell migration in tissue culture is an artefact of integrin processing, or whether such integrin dependent cell migration also occurs in living organisms.
Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinases that are indirectly and temporarily connected with the intracellular end of the integrin molecule, likely following shape changes directly stimulated by ECM binding.
The signals the cell receives through the integrin can have relation to:
- cell growth,
- cell division,
- cell survival,
- cellular differentiation, and
- apoptosis (programmed cell death).
The following are some of the integrins found in vertebrates:
|Î±4Î²1||VLA-4||Hematopoietic cells||Fibronectin, VCAM-1|
|Î±5Î²1||VLA-5; fibronectin receptor||widespread||fibronectin and proteinases|
|Î±6Î²1||VLA-6; laminin receptor||widespread||laminins|
|Î±MÎ²2||Mac-1, CR3||Neutrophils and monocytes||Serum proteins, ICAM-1|
|Î±IIbÎ²3||Fibrinogen receptor; gpIIbIIIa ||Platelets||fibrinogen, fibronectin|
|Î±VÎ²1||ocular melanoma; neurologial tumors||vitronectin; fibrinogen|
|Î±VÎ²3||vitronectin receptor||activated endothelial cells, melanoma, glioblastoma||vitronectin, fibronectin, fibrinogen, osteopontin, Cyr61|
|Î±VÎ²5||widespread, esp. fibroblasts, epithelial cells||vitronectin and adenovirus|
|Î±VÎ²6||proliferating epithelia, esp. lung and mammary gland||fibronectin; TGFÎ²1+3|
|Î±VÎ²8||neural tissue; peripheral nerve||fibronectin; TGFÎ²1+3|
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors â also by inducing a shape change â to trigger outside-in signal transduction.
- Xiong JP, Stehle T, Diefenbach B, et al. (October 2001). "Crystal structure of the extracellular segment of integrin alpha Vbeta3". Science 294 (5541): 339â45. doi:10.1126/science.1064535. PMC 2885948. PMID 11546839.
- Sauer FG, FÃ¼tterer K, Pinkner JS, Dodson KW, Hultgren SJ, Waksman G (August 1999). "Structural basis of chaperone function and pilus biogenesis". Science 285 (5430): 1058â61. doi:10.1126/science.285.5430.1058. PMID 10446050.
- Humphries M.J. (2000). "Integrin structure". Biochem. Soc. Trans. 28 (4): 311â339. doi:10.1042/0300-5127:0280311. PMID 10961914.
- Nermut MV, Green NM, Eason P, Yamada SS, Yamada KM (December 1988). "Electron microscopy and structural model of human fibronectin receptor". EMBO J. 7 (13): 4093â9. PMC 455118. PMID 2977331.
- Hynes R (2002). "Integrins: bidirectional, allosteric signaling machines". Cell 110 (6): 673â87. doi:10.1016/S0092-8674(02)00971-6. PMID 12297042.
- Xiong JP; Stehle, T; Diefenbach, B; Zhang, R; Dunker, R; Scott, DL; Joachimiak, A; Goodman, SL et al. (2001). "Crystal structure of the extracellular segment of integrin Î±vÎ²3". Science 294 (5541): 339â345. doi:10.1126/science.1064535. PMC 2885948. PMID 11546839.
- Smith J (2003). "Cilengitide Merck". Curr Opin Investig Drugs 4 (6): 741â5. PMID 12901235.
- Calderwood DA (June 2004). "Talin controls integrin activation". Biochem. Soc. Trans. 32 (Pt3): 434â7. doi:10.1042/BST0320434. PMID 15157154.
- Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH (October 1999). "The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation". J. Biol. Chem. 274 (40): 28071â4. doi:10.1074/jbc.274.40.28071. PMID 10497155.
- Shattil SJ, Kim C, Ginsberg MH (2010). "The final steps of integrin activation: the end game". Nat Rev Mol.Cell Biol. 11 (4): 288â300. doi:10.1038/nrm2871. PMID 20308986.
- Goldmann WH, Bremer A, HÃ¤ner M, Aebi U, Isenberg G (1994). "Native talin is a dumbbell-shaped homodimer when it interacts with actin". J. Struct. Biol. 112 (1): 3â10. doi:10.1006/jsbi.1994.1002. PMID 8031639.
- Harburger DS, Bouaouina M, Calderwood DA (April 2009). "Kindlin-1 and â2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects". J. Biol. Chem. 284 (17): 11485â97. doi:10.1074/jbc.M809233200. PMC 2670154. PMID 19240021.
- Olberding JE, Thouless MD, Arruda EM, Garikipati K (2010). "The non-equilibrium thermodynamics and kinetics of focal adhesion dynamics". In Buehler, Markus J. PLoS ONE 5 (8): e12043. doi:10.1371/journal.pone.0012043. PMC 2923603. PMID 20805876.
- Patla I, Volberg T, Elad N, Hirschfeld-Warneken V, Grashoff C, FÃ¤ssler R, Spatz JP, Geiger B, Medalia O (September 2010). "Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography". Nat. Cell Biol. 12 (9): 909â15. doi:10.1038/ncb2095. PMID 20694000.
- Gullingsrud J, Sotomayor M. "Mechanosensitive channels". Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology: University of Illinois at Urbana-Champaign.
- Benjamin Lewin (2007). Cells. Jones & Bartlett Learning. pp. 671â. ISBN 978-0-7637-3905-8. Retrieved 26 November 2010.
- Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004). Molecular cell biology (fifth ed.). New York: W.H. Freeman and CO. ISBN 0-7167-4366-3.
- http://www.vetpathology.org/cgi/reprint/34/1/61.pdf Vet Path01 34:61-73 (1997)
- Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, Caspary RG, Lindberg FP, Armitage R, Maliszewski C, Delespesse G, Sarfati M (February 1999). "The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23". J. Cell Biol. 144 (4): 767â75. doi:10.1083/jcb.144.4.767. PMC 2132927. PMID 10037797.
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Integrin beta tail domain Provide feedback
This is the beta tail domain of the Integrin protein. Integrins are receptors which are involved in cell-cell and cell-extracellular matrix interactions.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR012896
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [PUBMED:12297042, PUBMED:12361595]. The integrin receptors are composed of alpha and beta subunit heterodimers. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.
Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits [PUBMED:12234368]. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans [PUBMED:14689578]. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule [PUBMED:2467745]. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.
The structure of unliganded alphaV beta3 showed the molecule to be folded, with the head bent over towards the C termini of the legs which would normally be inserted into the membrane [PUBMED:12714499]. The head comprises a beta propeller domain at the end terminus of the alphaV subunit and an I/A domain inserted into a loop on the top of the hybrid domain in the beta subunit. The I/A domain consists of a Rossman fold with a core of beta parallel sheets surrounded by amphipathic alpha helices.
This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded beta-sheet that contains parallel and anttparallel strands and faces an alpha helix found at the N terminus of this domain [PUBMED:11546839]. Interactions between the alpha-helix and the beta-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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|Seed source:||Pfam-B_1876 (release 14.0)|
|Number in seed:||58|
|Number in full:||524|
|Average length of the domain:||83.70 aa|
|Average identity of full alignment:||32 %|
|Average coverage of the sequence by the domain:||9.93 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||7|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Integrin_B_tail domain has been found. There are 21 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...